Complex salt

ABSTRACT

A pharmaceutical composition containing a pharmacologically effective amount of a mixture of an alkali metal nitroprusside and a soluble trimethaphan salt in the weight ratio of less than 1:10.

CONTINUATION-IN-PART STATUS

This Application is a continuation-in-part of Ser. No. 456,128 filedJan. 6, 1983, the disclosure of which is incorporated by referencethereby.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to novel nitroprussides of short-acting ganglionicagents, particularly to the novel compoundbis-(trimethaphan)-nitroprusside and its (+)-isomer of formula ##STR1##and solvates, especially hydrates or alcoholates thereof, as well as aprocess for the manufacture thereof from an alkali nitroprusside and asoluble trimethaphan salt, especially sodium nitroprusside andtrimethaphan camsylate, in solution, especially in water.

The invention also relates to mixtures of an alkali metal nitroprusside,such as sodium nitroprusside, and a soluble salt of a short actingganglionic blocking agent, such as a soluble trimethaphan salt,particularly of (+)-trimethaphan. Trimethaphan camsylate or halogenide,such as the chloride or bromide, are also suitable.

The invention further relates to concentrated solutions (stocksolutions) containing said novel nitroprussides and mixtures.

Furthermore, the invention relates to pharmaceutical compositions whichcontain said novel nitroprussides and mixtures in solid form, in form ofconcentrated solutions or in form of diluted solutions suitable forinfusion purposes.

Preferred mixtures described are those containing the nitroprusside andthe salt of a short acting ganglionic blocking agent, especially oftrimethaphan or its (+)-isomer, in the weight ratio of 1:<10, especiallyin a ratio representing the nitroprusside salt of the ganglionicblocking agent, e.g., bis-(trimethaphan)-nitroprusside. Also describedare solutions, especially concentrated (stock) solutions of saidnitroprussides and mixtures in physiologically acceptable alcohols,especially in aqueous ethanol.

Also described are said nitroprussides, especiallybis-(trimethaphan)-nitroprusside, as well as its solvates, and saidmixtures, especially those of an alkali nitroprusside and a solubletrimethaphan salt, preferably in the weight ratio of less than 1:10,especially of about 1:4, when being dissolved in a physiologicallyacceptable alcohol, especially in aqueous ethanol, especially at least40% or preferably about 60% ethanol.

As was noted above, the invention relates to the use of the inventivecomposition in a weight ratio of less than 1:10, and preferably about1:4. The invention thus includes the range of 1:4-<10. Within thisrange, narrower ranges of 1:9, 1:8, 1:7, 1:6, and 1:5 may be listed byway of example. It is clear, of course, that although integers arelisted, intermediate ranges are also possible within the range set forthabove.

Preferably, these nitroprussides and mixtures are stored in the solidform and dissolved in said alcohol immediately before use. In such acase the alcohol may, in addition, contain other physiologicallyacceptable alcohols, such as polyols, like glycerol, inositol,pentaerythritol, mannitol or isosorbitol as well as nitrates, likemono-, di-, tri- or tetranitrates, thereof, especially nitroglycerin,preferably in an amount not exceeding the amount of nitroprusside to bedissolved, as well as nucleosides, such as inosine and adenosine, shortacting positive inotropic agents, such as dopamine or dobutamine, aphysiologically acceptable thiosulfate, such as sodium thiosulfate, ornicotinic acid and/or its biological precursors, likebeta-pyridylcarbinol.

The invention further relates to preparation of infusion solutions fromthe concentrated solutions or mixtures, the preparation of an especiallywell soluble micronized mixture of (I) and thiosulphate or of themixture of the salts and thiosulphate, and the use of the concentratefor the preparation of infusion solutions.

The compound (I), its solvates, the mixture of the salts, and thepharmaceutical compositions containing (I) or the mixture of the salts,are suitable for therapeutic use, particularly in the lowering of bloodpressure, in the achievement of peripheral vasodilation, in theelmination of arterial spasms and/or in the reduction of myocardialoxygen consumption and of the work load of the heart after heart attack.

2. Description of the Prior Art

Sodium nitroprusside is a known infusion preparation for the rapid andcontrolled lowering of the blood pressure in the case of operations orhypertensive crises and for reducing the work load of the heart, e.g.,in the case of heart attack. However, it has disadvantages whichrestrict the use of this valuable and extraordinarily well controllablemedicament. Thus, it decomposes in the body very rapidly with theformation of up to 5 moles of cyanide per molecule. Since cyanide is anacutely toxic agent which blocks the respiratory chain and paralyses therespiratory center, SNP must be used in order to avoid an accumulationof toxic cyanide concentrations in the blood serum only with thestrictest maintenance of prescribed highest dosages and even then onlyfor a short time.

In common with other vasodilators SNP has the disadvantage that thedesired rapid and powerful lowering of blood pressure leads veryfrequently to an activation of the so-called counter-regulation,whereby, in turn, the amount of circulating hormones which increaseblood pressure (adrenalin, noradrenalin and angiotensin II) and of reninis greatly increased. This causes, especially in young patients, astrong tendency to increased blood pressure which can be compensatedonly by successive increase of the dosage of SNP to be infused(tachyphylaxis). If in such cases the administration of SNP is notdiscontinued, a dangerous increase of the cyanide level in the bloodserum can arise very rapidly, even on short-term use of SNP, because ofthe over-dosage which then occurs. If in this case the tolerance limitof about 0.8 ug of CN/100 ml of blood plasma is exceeded, severe cyanidepoisoning and even death can arise (see Anesthesiology 47, 441-448(1977); Bull. Med. Legale Toxicol. 21, 215-224 (1978); Amer. J. Obstet.Gynecol. 139, 708-711 (1981).

A further disadvantage of SNP is the appearance of the so-called"rebound" hypertension owing to persistent counter-regulation aftertermination of the SNP infusion. (New England J. Med. 302, 1029-1030(1980); Anesthesiology 44, 345-348 (1976)). Since this "rebound"hypertension occasionally causes blood pressure levels which lie farabove the initial blood pressure, secondary bleedings can occur in newlyoperated patients and dangerous blood perfusion disorders in the brainowing to oedema formation can occur in predisposed patients.

Since, on the other hand, SNP is at present the most active agent forthe controlled lowering of blood pressure, e.g., during operations,attempts have been made to eliminate the mentioned disadvantages.

MacRae has recently proposed (Anaesthesia 36, 312-315 (1981)) to infusea very dilute solution containing SNP together with the ganglionicblocking agent trimethaphan camsylate (TMC), in the weight ratio 1:10.He reported that thereby the amount of SNP required for the samelowering of the blood pressure was considerably lower.

TMC and its blood pressure-lowering activity are known and TMC istherefore employed therapeutically (in spite of its lower activity)similarly to SNP, i.e., as an infusion preparation for the controlledshort-term lowering of blood pressure. However, TMC displays, in turn, aseries of side effects which restrict its use.

Thus, in addition to such side effects as tachycardia, mydriasis,cycloplegia, urine retention, xerostomia and constipation, which occurby blockade of the parasympathetic ganglia, nausea or vomiting can arisein sensitive patients and, especially in children and aged patients,allergies can arise owing to histamine liberation.

Moreover, trimethaphan camsylate must not be used alone in the case ofoperations in the region of the gastrointestinal tract.

The dosage of SNP required for the controlled lowering of blood pressureis on average about 3 ug/kg body weight per minute, that of the TMCabout 30 ug/kg or more per minute. Corresponding to this ratio of thepharmacological activities the concentrations of the infusion solutionsusually used are thus 0.01 and 0.1%, respectively. According to Table 2of MacRae (loc. cit.) a ratio of the dose rates of 1:14 and of the totaldosage of 1:10 correspond to the relative strengths of the two agents.

According to MacRae, the clinical activities of the single components indilute infusion solution containing SNP and TMC in the weight ratio of1:10 appear to be additive or even become potentiated, while thecorresponding side-effects (because of their qualitative difference) arerelatively diminished. Thus, seeing that ad hoc preparation of thedilute infusion solution containing such a mixture in the clinic iscomplicated and, because of the errors which are possible in practice,even dangerous, it appeared advantageous to develop appropriatecombination products as well as concentrates thereof which arerelatively stable and could easily be diluted to infusion strength.

An additional obstacle to the development of a combination product ofnitroprusside and trimethapan was the fact that the two single drugs arenot compatible in water and purely aqueous solvents in concentrated form[see for example the solubilities given in Example 10]. When preparingan aqueous solution of the mixture either drug had firstly to be dilutedto infusion strength, and these solutions could then be mixed shortlybefore the infusion. Because of the limited storage stability of dilutesolutions of TMC and SNP and because of the known extreme lightsensitivity of SNP solutions, such a highly diluted combination produceis, in any event, not suitable as a commercial product.

The observation that the hitherto unknown nitroprussides of short-actingganglionic agents, such as sulfonium and ammonium bases, for example,pentolinium and tetraethylammonium and, especially, trimethaphan, can beisolated in pure form and in high yield and can be processed to astorable pharmaceutical composition was therefore suprising.

It was also unknown and unobvious that these salts can form solvates andconcentrated aqueous alcoholic solutions, especially in view of theirlimited solubility in water.

It was also not obvious that mixtures of an alkali nitroprusside, suchas sodium nitroprusside, and a water-soluble salt of such a short-actingganglionic blocking agent as trimethaphan camsylate or a halogenide,e.g., the chloride or bromide, could be dissolved in aqueous ethanol andthat such solutions, in addition, may contain other physiologicallyacceptable alcohols, such as polyols, like glycerol, inosotol,pentaereythol, mannitol, or isosorbitol as well as nitrates, like mono-,di-, tri- or tetranitrates thereof, especially nitroglycerin, preferablyin an amount not exceeding the amount of nitroprusside to be dissolved,as well as nucleosides, such as inosine and adenosine, short-actingpositive inotropic agents, such as dopamine or dobutamine, aphysiologically acceptable thiosulfate, such as sodium thiosulfate ornicotinic acid and/or its biological precursors, likebeta-pyridylcarbinol.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided novelcomplex salts (adducts) of nitroprusside and short-acting ganglionicblocking agents, such quaternary sulfonium or ammonium bases, forexample, pentolinium, tetraethylammonium, or especially trimethaphan orits (+)-isomer, solid compositions containing these, as well asconcentrates thereof.

Particularly, in accordance with the present invention, there isprovided the complex salt bis-(trimethaphan)-nitroprusside of formula:##STR2## especially in the form of its (+)-isomer, which compounds arenovel and possess interesting pharmacodynamic properties.

Also there are provided solid compositions (mixtures) of an alkalinitroprusside, especially sodium nitroprusside, and the soluble salt ofa short-acting ganglionic agent, especially of trimethaphan or its(+)-isomer, in particular the camsylate or a halogenide, such as thechloride or bromide thereof, as well as concentrated solutions (stocksolutions) containing said novel nitroprussides and compositions.

Furthermore, there are claimed pharmaceutical compositions which containthe novel active substance (I) in solid form, in form of concentratedsolutions, or in form of diluted solutions suitable for infusionpurposes.

Preferred mixtures claimed are those containing the nitroprusside andthe salt of a ganglionic blocking agent, especially of trimethaphan orits (+)-isomer, in the weight ratio 1:<10, especially in a ratiorepresenting the nitroprusside salt of the ganglionic blocking agent,e.g., bis-(trimethaphan)-nitroprusside. Also described are solutions,especially concentrated (stock) solutions of said nitroprussides andmixtures in physiologically acceptable alcohols, especially in aqueousethanol.

Also claimed are the nitroprussides, especiallybis-(trimethaphan)-nitroprusside, as well as its solvates, and saidmixtures, especially those of an alkaline nitroprusside and a solubletrimethaphan salt, preferably in the weight ratio 1:<10, especially ofabout 1:4 when being dissolved in a physiologically acceptable alcohol,especially in aqueous ethanol, especially at least 40% or preferablyabout 60% ethanol.

Preferably, these nitroprussides and mixtures are stored in the solidform and dissolved in the alcohol immediately before use. In such acase, the alcohol may, in addition, contain other physiologicallyacceptable alcohols, such as polyols, like glycerol, inositol,pentaerythritol, mannitol, or isosorbitol as well as nitrates, likemono-, di-, tri or tetranitrates thereof, especially nitroglycerin,preferably in an amount not exceeding the amount of nitroprusside to bedissolved, as well as nucleosides, such as inosine and adenosine,short-acting positive inotropic agents, such as dopamine or dobutamine,a physiologically acceptable thiosulfate, such as sodium thiosulfate ornicotinic acid and/or its biological precursors, likebeta-pyridylcarbinol. Such mixtures are also novel and constitute oneaspect of the invention.

The invention also relates to solvates, particularly hydrates andalcoholates, of said novel nitroprussides, the manufacture of thesecompounds, pharmaceutical compositions containing such compounds and themanufacture of such compositions, as well as the use of such compoundsand of such pharmaceutical compositions in the controlled lowering ofblood pressure, in the achievement of peripheral vasodilation, in theelimination of arterial spasms and/or in the reduction of myocardialoxygen consumption and of the work load of the heart after heart attack.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the solution volumes for 50 mg. of I at room temperature inethanol-water mixtures of various concentrations;

FIG. 2 shows the face phase separation temperature of a solution of 50mg. of I and 1000 mg. of sodium thiosulfate pentahydrate in 55% ethanolas a function of the concentration; and

FIG. 3 shows the separation temperatures of a solution of 50 mg. of Iand 500 mg. of sodium thiosulfate pentahydrate in 50% ethanol as afunction of the concentration.

FIG. 4 shows a comparison of equieffective doses of(+)-bis-(trimethaphan)-nitroprusside, SNP, TMC, a combination of SNP andTMC in a weight ratio of 1:10; and a combination of SNP and TMC in aweight ratio of 1:4.

DETAILED DESCRIPTION OF THE INVENTION

The compound of formula I, above, has the advantage that it is free frompharmacologically inactive material (sodium and camsylate ions), so thatit has a considerably higher content of active material per weight unit:1000 mg of the compound (I) in accordance with the invention contain thesame amount of active material as 1575 mg of a mixture of 2 moles of TMCand 1 mole of SNP, which is also part of the invention. Such a reductionof the content of pharmaceutically inactive material can improve thetolerance of infusion preparations quite considerably.

Furthermore, the surprising and unforeseeable pharmacological findingwas made that not a very dilute infusion solution of the mixture ofequipotent amounts by weight (1:10) used by MacRae, but a solutioncontaining nitroprusside and trimethaphan ions in the molar ratio (1:2)present in the compound of formula (I) gives the maximum synergisticactivity. This is evident, for example, from the following experiment:

The various infusion solutions listed below were infused i.v. insuccession, with appropriate recovery intervals, into a male,spontaneously respiring cat weighing 3.7 kg under Nembutal narcosis, andthe dosages required to achieve a given lowering of the blood pressurewere determined.

    ______________________________________                                        Substances and mixtures of substances tested                                  ______________________________________                                        A   (+)-Bis-(trimethaphan)-nitroprusside                                      B   SNP (commerical product NIPRIDE)                                          C   TMC (commerical product ARFONAD)                                          D   The combination [mixture] of SNP and TMC [weight ratio                        1:10, the ratio of SNP and TMC present in the infusion                        solution used by MacRae et al. - 12.5 mg of SNP plus                          125 mg TMC in 500 ml of 5% dextrose solution]                             E   The combination mixture of SNP and TMC (weight ratio                          1:4)                                                                      ______________________________________                                    

For the preparation of the infusion solutions, the substances or theirconcentrated stock solutions were diluted with 0.9% sodium chloridesolution to a uniform infusion strength of 9 mg/100 ml (90 ug/ml). Allsolutions were freshly prepared and infused with the exclusion of light(aluminium foil) corresponding to the dosages given below.

The values given in Table I hereinafter were determined graphically.

                  TABLE I                                                         ______________________________________                                        Infusion dosages (ug/kg · min) of the compounds A to E               required to achieve a given lowering of the blood pressure                    Lowering of                                                                             (Infusion dosage required for this effect                           blood pressure                                                                          in ug/kg · min)                                            (in mm Hg)                                                                              A         B      C      D     E                                     ______________________________________                                        -20       1.5       1.7    6.0    4.3   2.9                                   -30       2.3       3.6    18     10    5.1                                   -40       3.5       7.0    55     29    8.6                                   -50       5.8       23     *      110   11.4                                  -55       7.8       75     *      *     27                                    -75       40        *      *      *     *                                     ______________________________________                                         * = Limit of activity and/or predominance of toxic side effects          

From Table I the following conclusions can be drawn:

In the case of slight lowering of the blood pressure (to -30 mm Hg) A, Band E still have approximately comparable strengths of activity,although even in this range A surprisingly shows up best. In the case ofgreater lowerings of the blood pressure (and at the same time greaterincreases of the counter-regulation) not only B but also E distinctlyfall off increasingly.

At about -55 mm Hg not only B but also E have reached the limit of theiractivity, i.e., with further increase in dosage only their toxic actionincreases.

C (TMC) is, as expected, significantly less active and reaches its limitof activity already at -40 mm Hg. D, the mixture of SNP and TMC (1:10)recommended by MacRae (loc. cit.), was also distinctly less active thanSNP (B) alone. The limit of activity was in the case of D -50 mm Hg,however D was distinctly more active than C (TMC alone).

It was also surprising that A has a significantly higher limit ofactivity than all the other substances or mixtures.

FIG. 4, a comparison of equieffective doses of A, B, C, D and E, isderived from the figures in Table I, and further indicates the unobvioussuperiority of infusion solutions having a weight ration of less than1:10 of the salts.

On the Y-axis, the weight percent of the trimethaphan ion intrimethaphan camsylate needed to achieve the indicated level ofhypotension reduction is always set at 100% for each level, indicatingthe infusion solution of C. The X-axis measures the weight ofnitroprusside ion expressed as a weight percent of the trimethaphan ionneeded; B, having no trimethaphan, is set at 0 weight percent. Thepercents for A, D, and E are as indicated.

The numbers with an asterisk are the absolute infusion rates of B and Ctaken from Table I of the application.

The hypotenuse of the triangle indicates the hypotensive effect expectedto result from using mixtures of nitroprusside and trimethaphan ions.All values within the triangle demonstrate synergism. The lower and moreto the left the values are, the higher the degree of synergism.

The dotted line shows the MacRAE ratio of 1:10, and the space betweenthe dotted line and the hypotenuse indicates the synergism made obviousby MacRAE.

The shaded area indicates synergism not obvious from MacRAE.

FIG. 4 shows that as the level of blood pressure reduction increases,the area of the space between the dotted line and the hypotenusedecreases in comparison to the shaded area. Thus, as indicated by thetables shown previously, the graph demonstrates a trend of increasingdiscrepancy between the synergism of mixtures of less than 1:10 weightratio, and the synergism of 1:10 mixtures. Thus, as was noted above, theinvention relates to the use of the inventive composition in a weightratio of less than 1:10, and preferably about 1:4. The invention thusincludes the range of 1:4-<10. Within this range, narrower ranges of1:9, 1:8, 1:7, 1:6, and 1:5 may be listed by way of example. It isclear, of course, that although integers are listed, intermediate rangesare also possible within the range set forth above.

Such data are unquestionable proof of the unobvious properties of thebis-(trimethaphan)-nitroprusside in isolated form, and of thenitroprusside and trimethaphan salts in the weight ratio of less than1:10.

In accordance with the present invention, nitroprussides of short-actingganglionic blocking agents, especially bis-(trimethaphan)-nitroprussideand solvates thereof can be prepared by reacting a solution of an alkalinitroprusside with a soluble salt of a short-acting ganglionic agent,such as pentolinium, tetramethyl-ammonium or especially of a solubletrimethaphan salt, and, if desired, separating the less soluble productfrom the more readily soluble accompanying salts and isolating saidproduct.

The reaction is conveniently carried out in a solvent containing thedesired solvating agent, particularly in aqueous solution or in asolution which contains water and/or alcohol. In a preferred embodimentof the process of the invention, sodium nitroprusside and trimethaphancamsylate are brought together in aqueous solution, and the less solublecrystalline bis-(trimethaphan)-nitroprusside is isolated if desired.

The present invention is also concerned with pharmaceutical compositionswhich contain the novel active substancebis-(trimethaphan)-nitroprusside (I) in concentrated form or in diluteform suitable for infusion purposes, processes for their manufacture aswell as their therapeutic use.

In a preferred embodiment of its composition aspect, the invention isconcerned with a concentrated stock solution of I in at least 40%ethanol, which can also be prepared in situ from an appropriate amountof I (contained, for example, in a vial or a dry ampoule) and a smallamount of at least 40% ethanol (contained, for example, in a sterileampoule), whereby the ethanol is preferably 50 to 95, especially about60%. The amount of solvent for the preparation of the stock solutionpreferably amounts to at most 20 ml, especially 2-5 ml.

A dilute (about 0.01%) infusion solution can be prepared from theconcentrated stock solution at the place of use with a sterileconventional infusion liquid, such as 0.9% sodium chloride solution or5% glucose solution. The dilute infusion solutions of the activesubstance I are also part of the invention.

The present invention also relates to solid compositions (mixtures) ofan alkali nitroprusside, especially sodium nitroprusside, and a solublesalt of a short-acting ganglionic agent, especially of trimethaphan orits (+)-isomer, in particular the camsylate or a halogenide, such as thechloride or bromide thereof, as well as concentrated solutions (stocksolutions) containing said novel nitroprussides and compositions.

Preferred mixtures are those containing the nitroprusside and the saltof a ganglionic blocking agent, especially of trimethaphan or its(+)-isomer, in the weight ratio 1:<10, especially in a ratiorepresenting the nitroprusside salt of the ganglionic blocking agent,e.g., bis-(trimethaphan)-nitroprusside. Also described are solutions,especially concentrated stock solutions, of said nitroprussides andmixtures in physiologically acceptable alcohols, especially in aqueousethanol.

Also claimed are the nitroprussides, especiallybis-(trimethaphan)-nitroprusside, as well as its solvates, and saidmixtures, especially those of an alkali nitroprusside and a solubletrimethaphan salt, preferably in the weight ratio of 1:<10, especiallyof about 1:4 when being dissolved in a physiologically acceptablealcohol, especially an aqueous ethanol, especially at least 40% orpreferably about 60% ethanol.

Preferably, these nitroprussides and mixtures are stored in a solid formand dissolved in said alcohol immediately before use. In such a case,the alcohol may, in addition, contain other physiologically acceptablealcohols, such as polyols, like glycerol, inositol, pentaerythritol,mannitol, or isosorbitol, as well as nitrates, like mono-, di-, tri- ortetranitrates, thereof, especially nitroglycerin, preferably in anamount not exceeding the amount of nitroprusside to be dissolved, aswell as nucleosides, such as inosine and adenosine, short-actingpositive inotropic agents, such as dopamine or dobutamine, aphysiologically acceptable thiosulfate, such as sodium thiosulfate, ornicotinic acid and/or its biological precursors, likebeta-pyridylcarbinol. Such solutions are also part of this invention.

The mixture of I and thiosulphate should be present preferably at leastin the weight ratio 1:1 and preferably at most in the weight ratio 1:40.

The pharmaceutical infusion solutions obtained from the aboveconcentrates or solid mixtures according to the processes describedbelow serve, for example, for the rapid and controlled lowering of bloodpressure, for the peripheral vasodilation, for the elimination ofarterial spasms and for the reduction of the myocardial oxygenconsumption and of the work load of the heart after heart attack.

The compound I contains the nitroprusside anion which is also present insodium nitroprusside.

In the case of the therapeutic administration of the novel compound Iand of the mixtures and solutions described above, the danger of cyanidepoisoning is considerably lower, since I contains a lower amount byweight of cyanide (13.7%) than SNP (43.6%) and, moreover, it can beadministered at lower dosages then SNP. However, the latent danger of anaccumulation of dangerous amounts of cyanide in the plasma still existsin particular circumstances (e.g., in patients with greatly reducedendogenous thiosulphate level or owing to exhaustion of the endogenousthiosulphate reserves in the case of long term application, high dosagesor in the case of erroneous over-dosage). It is also known that higherplasma concentrations of cyanide (>10⁻⁵ ug/ml) can greatly impair thevasodilatory activity of SNP (Amer. J. Physiol. 237, H185-H190 (1979)).Therefore, high cyanide concentrations in the plasma are considered asbeing a factor responsible for the occurrence of tachyphylaxis duringthe therapeutic administration of SNP (Anesthesiology 51, 563-564(1979)).

It is known that the toxicity of SNP can be reduced, e.g., in mice andrabbits, by simultaneous infusion of sodium thiosulphate (J. Pill, P.Engeser, M. Hobel, V. A. W. Kreye, Toxicology Letters, Suppl. 1, 156, p.61 (1981)). These authors also proposed to use SNP and sodiumthiosulphate in stoichiometric amounts (1:5 mol), i.e., to employ theseagents in the weight ratio 1:4.16, whereby SNP is employed as thedihydrate (m.w. 298) and sodium thiosulphate is employed as thepentahydrate (m.w. 248.1).

The use of thiosulphate as a cyanide antidote has been known for a longtime and is based on the fact that thiosulphate is the substrate of theenzyme rhodanase which converts cyanide into the not very toxicthiocyanate.

It therefore appears advantageous also to administer the compound Isimultaneously with an amount of a water-soluble thiosulphate equivalentto the biologically liberated amount of cyanide.

In order to facilitate the control of the correct dosage for thephysician, there comes into consideration for this purpose a uniformpharmaceutical composition (mixture) of I and thiosulphate, which, ifdesired, is already dissolved or can be brought into solution in asimple manner.

Suitable thiosulphates are in principle all physiologically acceptablethiosulphates which are soluble in water and in aqueous ethanol, such asalkali thiosulphates, e.g., potassium thiosulphate or sodiumthiosulphate or its pentahydrate. However, sodium thiosulphate has to begiven preference on practical reasons, because it is pharmacologicallyand clinically tested, has a very low toxicity (LD₅₀ in rats, i.v., 2500mg/kg) and is furthermore readily obtainable.

Corresponding to the amount of nitroprusside anion there can be formedfrom one mol of I (m.w.=947) 5 mol of cyanide, for the detoxification ofwhich 5 mol of thiosulphate suffice in theory. The stoichiometric ratio(by weight) of I and sodium thiosulphate pentahydrate is thus 1:1.31 andthe weight of sodium thiosulphate pentahydrate equivalent to the cyanidefrom 50 mg of I amounts to only 65.5 mg. This amount is thussignificantly lower than the amount of sodium thiosulphate pentahydrate(208 mg) theoretically required for 50 mg of SNP.

Sodium thiosulphate is, however, used as a cyanide antidote (i.e., inthe treatment of acute cyanide poisoning) in considerable excess, e.g.,in dosages of 1 g up to 12.5 g, which have to be injected in aqueoussolution and very slowly.

This excess is necessary in urgent cases of acute cyanide poisoning,since thiosulphate passes through biological membranes only very slowlyand yet must be available rapidly and in large amount. However, thedosage can be reduced quite considerably in the case of prophylacticuse. On the other hand, a certain excess is necesary, since thiosulphateis excreted relatively rapidly via the kidneys. It is thereforerecommendable to use a multiple of the calculated stoichiometricthiosulphate dosage, e.g., up to 2000 mg per 50 mg of I (weight ratio1:40).

For reasons of storage stability, medicaments intended for infusion arefrequently marketed not as solutions, but in solid form. For obtainingan unobjectionable solution it is usual in such cases to prepare bymeans of a supplied solvent ampoule immediately prior to use a smallamount of a concentrated solution and to dilute this to the infusionstrength immediately.

It has been shown that thiosulphate is indeed suitable for thepreparation of a purely aqueous concentrated stock solution, but not theactive substance I or a mixture thereof with thiosulphate:

FIG. 1 shows the solution volumes for 50 mg of I at room temperature(22° C.) in ethanol-water mixtures of various concentrations.

As is evident from FIG. 1, at least 40% ethanol is required for thepreparation of a concentrated stock solution of I. On the other hand,sodium thiosulphate displayed only very limited solubility in over 40%ethanol, especially at temperatures <50° C. Mixtures of I andthiosulphate must not however, be heated in solution above 50° C., sinceotherwise the trimethaphan cation can decompose.

Therefore, the problem arose to find a physiologically acceptablesolvent in which a mixture of I and thiosulphate in the weight ratio ofabout 1:1 to about 1:40 can dissolve to at least 5-10%, in a temperaturerange which for practical reasons should embrace temperatures betweenabout 15° C. and about 35° C. Moreover, the concentrated solution shouldbe able to dissolve without problem in the amount (250-1000 ml) ofphysiological sodium chloride solution or isotonic (5%) glucose solutionrequired for final dilution.

Alternatively, a way was to be sought to enable the mixture of I andthiosulphate to be dissolved directly, rapidly and reliably in largevolumes of the aforesaid infusion liquids with the avoidance of stocksolutions.

It has now been found that 40-60% ethanol is suitable as a solvent forthe preparation of concentrated stock solutions of mixtures of I andsodium thiosulphate up to a weight ratio 1:20 of the components.

For example, the mixture of 50 mg of I and 1000 mg of sodiumthiosulphate pentahydrate dissolved

at 37° C. in 10 ml

at 25° C. in 12 ml

at 20° C. in 13 ml and

at 15° C. in 15 ml of 55% ethanol.

Below the above-mentioned temperatures separation into two phasesoccurred immediately and thiosulphate crystallized out after a shorttime.

FIG. 2 shows the phase separation temperature of a solution of 50 mg ofI and 1000 mg of sodium thiosulphate pentahydrate in 55% ethanol as afunction of the concentration.

In 50% ethanol the same mixture dissolved at 25° C. already in 8 ml.However, when it was cooled to temperatures below 22° C., phaseseparation occurred.

Thiosulphate has indeed a better solubility in weaker ethanol, but I isno longer completely soluble.

On the other hand, if the amount of thiosulphate in the mixture wasreduced, then less or more concentrated ethanol (40-70%) could also beused for the preparation of a concentrated stock solution.

FIG. 3 shows the separation temperatures of a solution of 50 mg of I and500 mg of sodium thiosulphate pentahydrate in 50% ethanol as a functionof the concentration.

As FIG. 3 shows, a mixture in the weight ratio 1:10 (50+500 mg) alreadyhas a very good solubility in 50% ethanol: the latter mixture dissolvedin accordance with FIG. 3 above 15° C. already in 5 ml of 50% ethanol.

The thus-obtained concentrated aqueous-alcoholic solutions dissolvedwithout turbidity when poured into 220 ml of 0.9% sodium chloridesolution or 5% glucose solution, thus their practical applicability isdemonstrated.

The addition of a physiologically accepted alcohol is not adisadvantage. A small amount of ethanol does not interfere with theinfusion, but rather brings about an additional slight vasodilatoryeffect, and is thus an acceptable solution to the problem describedabove.

If the amount of thiosulphate is increased to above 1000 mg per 50 mg ofI, then a concentrated stock solution in above 40% ethanol-watermixtures can no longer be prepared at 15° C.

However, it has surprisingly been found that in this case a directsolution of the mixture in the given amount of 0.9% sodium chloridesolution or 5% glucose solution is possible when it is used in finestpulverized form, at best in micronized form. It has been found that amicronized mixture of 50 mg of I and 2000 mg of sodium thiosulphatepentahydrate dissolves within a few seconds in 250 ml of 5% glucosesolution, while a coarsely ground mixture dissolved only after shakingfor more than 10 minutes.

The methods in accordance with the invention described above thus enablenot only the compound I, which is poorly soluble in water, but alsomixtures of I and thiosulphate to be converted in a reliable manner intocorresponding infusion solutions.

Bis-(trimethaphan)-nitroprusside and the solid mixtures, as well astheir alcoholic solutions needed to prepare the concentrated [stock]solutions described above, can be stored without further additives, whenlight is excluded and room temperature is not permanently exceeded.

The following Examples illustrate the present invention but are notintended to limit its extent. In these Examples all temperatures aregiven in degrees Centigrade.

EXAMPLE 1

29.8 g (0.1 mol) of sodium nitroprusside dihydrate are dissolved in 500ml of water at room temperature. The reddish brown solution (solution A)obtained has to be protected from light.

119.4 g (0.2 mol) of (+)-trimethaphan camsylate are dissolved in 2000 mlof water and this solution is placed in a 3 l wide-necked vessel whichis protected from light with aluminum foil. The solution A is addeddropwise at room temperature with stirring and with occasional additionof seed crystals (or with occasional scratching). The velocity of thedropwise addition and the velocity of the stirring influence the size ofthe separating white to slightly yellowish crystals. The crystals aresucked off, rinsed several times with water and dried with the exclusionof light in vacuo at temperatures below 50°.

The compound thus obtained, (+)-bis-(trimethaphan)-nitroprusside, isonly very slightly soluble in water, absolute ethanol and cyclohexane,but dissolves readily in aqueous ethanol.

If necessary, the compound can be recrystallized from aqueous ethanol orfrom methanol, optionally with addition of diethyl ether. Onrecrystallization from 70% ethanol there are obtained fine,yellowish-white needle clusters of melting point 200°-203°(decomposition).

The compound is solvated depending on the solvent used. Elementalanalysis (after drying, 18 h at room temperature/10⁻³ Torr overSiccapent):

    ______________________________________                                        C.sub.49 H.sub.50 O.sub.3 N.sub.10 S.sub.2 Fe Molecular weight                ______________________________________                                        947.0                                                                         Calculated                                                                            C 62.15 H 5.32  N 14.79                                                                              S 6.77                                                                              H.sub.2 O --                                                                         (%)                               Found   61.75   5.48    14.83  6.89  0.65   (%)                               ______________________________________                                    

Systematic name:(+)-bis-/(3aS,8aR,8bR)-1,3-dibenzyldecahydro-2-oxoimidazo[4,5-c]thieno[1,2-a]thiolium/nitrosylpentacyano-ferrate.

The semihydrate forms compact needles from water (1/2H₂ O calculated0.94%, found 1.00%). It is stable at storage at room temperature anddoes not lose water under these conditions. Its solubility in water is0.2% at room temperature. Its solubility in 60% ethanol is much better,and is about 3% at room temperature.

EXAMPLE 2

50 g of (+)-bis-(trimethaphan)-nitroprusside are dissolved at 25° in 2.8l of 60% ethanol. The volume of the solution is brought to 3 l. Afterfiltration over a Millipore filter, 3 ml portions of the solution arefilled into sterile solvent ampoules manufactured from brownpyrogen-free glass.

The ampoules can even be stored at room temperature with exclusion oflight. For the preparation of an infusion solution, the ampoule contentsare dissolved in at least 220, at most 900 ml of sterile 0.9% sodiumchloride solution or 5% glucose solution by vigorous shaking for a shorttime, whereafter the volume is brought to 250, 500 or 1000 ml. Theinfusion vessels and tubes are either to be covered with aluminum foilor must consist of material which is opaque to light.

The usual dosage amounts to 0.1-5 ug/kg.min, i.e., 0.5-100 ul/kg.min.depending on the concentration used.

EXAMPLE 3

50 mg of finely pulverized (+)-bis-(trimethaphan)-nitroprusside arefilled into a sterilized, brown 5 ml flask closable with a syntheticstopper. 3 ml of 60% ethanol are sealed in a solvent ampoule andsterilized. Both substances can be stored for a very long time at roomtemperature and with exclusion of light. Immediately before use thesolid substance is dissolved in the solvent and the thus-obtained stocksolution is used for the preparation of the infusion solution.

EXAMPLE 4

A micronized mixture of 50 mg of (+)-bis-(trimethaphan)-nitroprussideand 2000 mg of sodium thiosulphate pentahydrate is filled into a browndry ampoule or a brown vial supplied with a lid and stored at roomtemperature with exclusion of light.

Immediately before use the mixture is added with vigorous stirring orshaking to a measuring flask with at least 220 ml, at most 900 ml of0.9% sodium chloride solution or 5% glucose solution, whereafter thevolume is brought to 250, 500 or 1000 ml.

EXAMPLE 5

A finely pulverized mixture of 50 mg of(+)-bis-(trimethaphan)-nitroprusside and 250 mg of sodium thiosulphatepentahydrate is filled into a brown 5 ml solvent ampoule and 5 ml of 55%ethanol are added thereto. After closing, the ampoules are stored withthe exclusion of light.

EXAMPLE 6

A micronized mixture of 25 g of (+)-bis-(trimethaphan)-nitropruside and125 g of sodium thiosulphate pentahydrate is dissolved in 2.5 l of 50%ethanol. The volume of the solution is brought to 3 l. After sterilefiltration, 3 ml portions of the solution are filled into sterile,pyrogen-free brown solvent ampoules. The ampoules are sealed and storedwith exclusion of light.

Immediately before use the contents of one ampoule are dissolved in atleast 220 ml of 0.9% sodium chloride solution or 5% glucose solution andthe volume is brought to 250, 500 or 1000 ml. The infusion solution isto be protected from the effect of light.

If the mid concentration were chosen (i.e., if the volume were broughtto 500 ml), then the infusion dosage would amount in general to 2-100ul/kg.min.

EXAMPLE 7

A brown solvent ampoule containing 50 mg of(+)-bis-(trimethaphan)-nitroprusside dissolved in 60% ethanol is packedtogether with a colourless solvent ampoule containing 250 mg of sodiumthiosulphate dissolved in 3 ml of water. The ampoules are stored withexclusion of light.

Immediately before use the contents of the two ampoules are diluted withinfusion liquid up to a volume of 250, 500 or 1000 ml. The obtainedsolution is to be protected from the effects of light.

EXAMPLE 8

25 mg of finely ground (+)-bis-(trimethaphan)-nitroprusside are mixedwith 12.5 g of dry glucose. The mixture is ground again, if necessary,and then filled into a sterile PVC infusion bag or into a great dryampoule.

For preparing an infusion solution from the dry ampoule, the contents ofthe dry ampoule are dissolved in 220 ml of water, whereafter the volumeis brought to 250 ml.

For preparing an infusion solution in the infusion bag the contents ofthe infusion bag are dissolved by addition of 240 ml of water.

In both cases, the infusion solution contains(+)-bis-(trimethaphan)-nitroprusside in a concentration of 0.1 mg/ml (or0.1 ug/ul) and 5% of glucose.

EXAMPLE 9

13.8 mg (52.8 umoles) of anhydrous sodium nitroprusside, 42.3 mg (105.6umoles) of anhydrous (+)-trimethaphan chloride and 4.50 g of dry sodiumchloride are mixed and finely ground with exclusion of light. Themixture is filled into a dry ampoule or into a PVC infusion bag.

For preparing an infusion solution from the dry ampoule, the contents ofthe dry ampoule are added, immediately before the infusion, to 450 ml ofwater "pro injectionem" with vigorous stirring or shaking in order toprevent the poorly soluble (+)-bis-(trimethaphan)-nitropruside which isformed in situ in finely divided form, from precipitating in the form ofgreater particles. Thereafter the volume is brought to 500 ml.

For preparing an infusion solution in the infusion bag, the appropriateamount of water (496 ml) is given into the bag and the contents of thebag are dissolved by shaking.

In both cases the infusion solution contains 0.9% of sodium chloride and(+)-bis-(trimethaphan)-nitroprusside in a concentration of 50 mg.liter(or 50 ug/ml or 0.05 ug/ul).

EXAMPLE 10

At room temperature (22° C.) clear solutions were obtained in thefollowing solvents from the following compounds:

    ______________________________________                                                      5%         40%      60%                                                 Water Dextrose   Ethanol  Ethanol                                     ______________________________________                                        SNP (50 mg)                                                                              2 ml    2 ml       2 ml  3 ml                                      TMC (250 mg)                                                                            10 ml   10 ml      10 ml  2 ml                                      ______________________________________                                    

When the concentrated solutions of SNP and TMC in water or in 5%dextrose are mixed directly, a milky suspension originates immediatelyfrom which a syrup separates which eventually crystallizes after awhile.

This can only be brought in solution by stirring it in a very largeexcess of the aqueous solvent used (About 500 ml).

In the case of the 40% ethanol the deposit is smaller and much morereadily soluble in water or dextrose solution. In the case of the 60%ethanol no deposit is formed at all, not even after cooling to 0° C.

    ______________________________________                                        Solubility of Mixtures of SNP, TMC or of TNP                                                    5%       40%      60%                                                   Water Dextrose Ethanol  Ethanol                                   ______________________________________                                        SNP + TNP (1 + 10)                                                                          500 ml  500 ml   50 ml  3 ml                                    (50 + 500 mg)                                                                 SNP + TMC (1 + 4).sup.(o)                                                                   --      500 ml   --     10 ml                                   (125 + 500 mg)                                                                TNP*          --      100 ml.sup.(x)                                                                         25 ml  2 ml                                    (40 mg)                                                                       ______________________________________                                         .sup.(o) Preferred SNP/TMC mixture according to the invention                 .sup.(x) The solubility of a highly purified product is given here            .sup.(*.sup.) TNP (40 mg) has the same contents of the active ions (9.0 m     nitroprusside and 30.6 mg trimetaphan) as a mixture of 12.5 mg SNP and 50     mg TMC (weight ratio 1:4) which contains 9.06 mg. nitroprusside and 30.6      mg trimethaphanions.                                                     

The amounts of solvents given are borderline amounts which could notsignificantly be reduced without beginning precipitation of syrups orcrystals.

EXAMPLE 11

12.5 mg of finely ground sterile sodium nitroprusside dihydrate and 100mg sterile trimethaphan camsylate are mixed and filled into a 10 ml vialclosed with a caoutchouc stopper. An ampoule containing 3 ml sterile 60%ethanol was co-packed. After storage at or below 20° C., just beforeuse, the contents of the ampoule is injected under sterile conditionsthrough the caoutchouc stopper, the mixture dissolved by shaking, theresulting clear solution again taken up by means of an injection syringeand injected into 500 ml of 5% dextrose in water solution contained in asterile infusion bag.

The infusion rate should be 0.4 to 10 ug/kg. min according to the age ofthe patient and the degree of hypotension intended.

EXAMPLE 12

12.5 mg of hydrophilyzed sterile SNP and 50 mg of sterile TMC are mixedthoroughly and filled into a 10 ml vial, which can be treated as in Ex.11.

EXAMPLE 13

12.5 mg of finely powdered SNP and 40 mg racemic Trimethaphan bromideare mixed and filled into a 10 ml vial and then treated as described inEx. 11.

EXAMPLE 14

50 mg of SNP dihydrate and 55 mg Tetraethylammonium chloride are mixedand dissolved in 20 ml of 40% ethanol and then injected into 500 ml ofsterile 0.9% (physiological) sodium chloride solution and infused at arate of 2 to 15 ug/kg.min.

EXAMPLE 15

To 30 mg of finely ground SNP dihydrate and 54 mg pentolinium hydrogentartrate were added 10 ml of 95% ethanol, the suspension refluxed for 20minutes with exclusion of light and sucked off.

When the ethanolic filtrate was evaporated, ivory colored crystals ofpentolinium nitroprusside separated.

EXAMPLE 16

40 mg of bis-(trimethaphan)-nitroprusside semihydrate were dissolved in5 ml 60% ethanol, containing

(a) 40 mg nitroglycerin

(b) 40 mg nitroglycerin and 1000 mg glycerol, or

(c) 300 mg beta-pyridylcarbinol.

In any of these cases a clear solution resulted which could be dilutedto infusion strength with 500 ml of 5% dextrose in water infusionliquid.

Although the Examples have been given only to weight ratios of 1:4 and1:8, it is clearly understood, from Graph I, that synergisticallyimproved results are obtained in all concentrations of less than 1:10.

Although the invention has been described with respect to particularmeans, materials and embodiments, it is to be understood that theinvention is not limited to the particulars disclosed, and extends toall equivalents falling within the scope of the claims.

What is claimed is:
 1. A composition comprising a concentrated solution,in aqueous ethanol, of a pharmaceutically effective amount of anitroprusside of a short acting ganglionic blocking agent selected fromthe group consisting of sulfonium salts and ammonium salts.
 2. Aninfusion solution comprising, as an active substance, a pharmaceuticallyeffective amount of a nitroprusside of a short acting ganglionicblocking agent selected from the group consisting of sulfonium salts andammonium salts, and an infusion liquid.
 3. A pharmaceutical preparationcomprising two separate containers, the first container containing anamount of aqueous ethanol which is required to prepare a concentratedsolution of material in the second container when the first and secondcontainers are admixed, and the second container containing apharmaceutically effective amount of a nitroprusside of a short actingganglionic blocking agent selected from the group consisting ofsulfonium salts and ammonium salts, and solvates thereof.
 4. Apharmaceutical preparation of claim 3 wherein the first container alsocontains the following:(a) at least one member of the group consistingof physiologically acceptable alcohols other than ethanol, and nitratesthereof; (b) at least one nucleoside; (c) at least one short-actingpositive inotropic agent; and (d) at least one member of the groupconsisting of physiologically acceptable thiosulphates, nicotinic acid,and biological precursors of nicotinic acid.
 5. A composition comprisinga concentrated solution of a pharmaceutically effective amount ofpentolinium nitroprusside in aqueous ethanol.
 6. A pharmaceuticalpreparation comprising two separate containers, the first containercontaining a pharmaceutically effective amount ofbis-(trimethaphan)-nitroprusside, and the second container containing anamount of aqueous ethanol having an ethanol content of at least 40%which is required to prepare a concentrated solution of the material inthe first container when the two containers are admixed, the secondcontainer also containing the following:(a) at least one member of thegroup consisting of physiologically acceptable alcohols other thanethanol, and nitrates of said physiologically acceptable alcohols; (b)at least one nucleoside; (c) at least one short acting positiveinotropic agent; and (d) at least one member of the group consisting ofphysiologically acceptable thiosulphates, nicotinic acid, and biologicalprecursors of nicotinic acid.
 7. A composition comprising a concentratedsolution of a pharmaceutically effective amount of an alkali metalmitroprusside and a soluble salt of a short acting ganglionic blockingagent selected from the group consisting of sulfonium salts and ammoniumsalts in a physiologically acceptable alcohol.
 8. The composition ofclaim 7 wherein the alkali metal nitroprusside is sodium nitroprussideand the short acting ganglionic blocking agent is trimethaphancamsylate.
 9. A composition comprising a solid mixture of an alkalimetal nitroprusside and a soluble salt of a short-acting ganglionicblocking agent selected from the group consisting of sulfonium salts andammonium salts.
 10. A composition comprising a concentrated solution ofthe composition of claim 9 in aqueous ethanol.
 11. An infusion solutioncomprising, as an active substance, a pharmaceutically effective amountof the composition of claim 9 and an infusion liquid.
 12. Apharmaceutical preparation comprising two separate containers, the firstcontainer containing an amount of aqueous ethanol which is required toprepare a concentrated solution of the material in the second containerwhen the first and second containers are admixed, and the secondcontainer containing a pharmaceutically effective amount of thecomposition according to claim
 9. 13. The pharmaceutical preparation ofclaim 12 wherein the first container also contains the following:(a) atleast one member of the group consisting of physiologically acceptablealcohols other than ethanol, and nitrates of said physiologicallyacceptable alcohols; (b) at least one nucleoside; (c) at least one shortacting positive inotropic agent; and (d) at least one member of thegroup consisting of physiologically acceptable thiosulphates, nicotinicacid, and biological precursors of nicotinic acid.
 14. The compositionof claim 9 wherein the alkali metal nitroprusside is selected from thegroup consisting of sodium nitroprusside and potassium nitroprusside.15. A composition comprising a concentrated solution of apharmaceutically effective amount of the composition of claim 14 inaqueous ethanol.
 16. The composition of claim 14 wherein the solublesalt of the short acting ganglionic blocking agent is atetraethylammonium salt.
 17. A composition comprising a concentratedsolution of a pharmaceutically effective amount of the composition ofclaim 16 in aqueous ethanol.
 18. The composition of claim 14 wherein thesoluble salt of the short acting ganglionic blocking agent is apentolinium salt.
 19. A composition comprising a concentrated solutionof a pharmaceutically effective amount of the composition of claim 18 inaqueous ethanol.
 20. The composition of claim 14 wherein the solublesalt of the short-acting ganglionic blocking agent is a trimethaphansalt selected from the group consisting of the camsylate and thehalogenide.
 21. A concentrated solution of the composition of claim 20in aqueous ethanol having an ethanol content of at least 40%.
 22. Apharmaceutical composition containing, as an active substance, thecomposition of claim
 20. 23. An infusion solution comprising, as anactive substance, a pharmaceutically effective amount of the compositionof claim 20 and an infusion liquid.
 24. The composition of claim 20wherein the akali metal nitroprusside and soluble trimethaphan salt arepresent in the weight ratio of less than 1:10.
 25. A concentratedsolution of a pharmaceutically effective amount of the composition ofclaim 24 in aqueous ethanol having an ethanol content of at least 40%.26. A pharmaceutical composition containing, as an active substance, thecomposition of claim
 24. 27. A composition comprising a mixture of anakali metal nitroprusside and a soluble trimethaphan salt in the weightratio of approximately 1:4.
 28. The composition of claim 27 which is asolid mixture.
 29. A concentrated solution of a pharmaceuticallyeffective amount of the composition of claim 27 in aqueous ethanolhaving an ethanol content of at least 40%.
 30. A pharmaceuticalcomposition containing, as an active substance, the composition of claim27.
 31. An infusion solution comprising, as an active substance, apharmaceutically effective amount of the composition of claim 27 and aninfusion liquid.